Multi‐Target Anti‐Inflammatory and Antioxidant Potential of Phloracetophenone 4‐ <i>O</i> ‐β‐ <scp>d</scp> ‐Glucopyranoside: Experimental Validation and Computational Mechanistic Insights

Abstract

ABSTRACT This research explores the biological activities and the structure–activity relationship of phloracetophenone 4‐ O ‐β‐ d ‐glucopyranoside ( 1 ). The antioxidant activity was assessed using four different techniques. The structure–activity relationship was studied through three primary mechanisms, namely, hydrogen atom transfer (HAT), sequential proton loss electron transfer (SPLET), and SET–PT, using BDE(E0), energy decomposition scheme (ETS)‐natural orbitals for chemical valence (NOCV), and BDE. Atoms in molecules (AIM) and key thermodynamic parameters were calculated using DFT. Moreover, the anti‐inflammatory potential was evaluated by its ability to inhibit ovalbumin denaturation, along with molecular docking against tumor necrosis factor‐alpha (TNF‐α), MAP kinase, cyclooxygenase‐1 (COX‐1), and COX‐2 targets. The molecule demonstrated high antioxidant activity in ferric thiocyanate test (FTC) (82.74%), reducing power (RP) ( A 0.5 = 15.9 µg/mL), total antioxidant capacity (TAC) (25.88 µg EAA/mg), and cupric reducing antioxidant capacity (CUPRAC) assays ( A 0.5 = 0.51 µg/mL). This correlation is consistent with theoretical predictions; the HAT mechanism was predominant in nonpolar environments, whereas SPLET was favored in polar solvents. Additionally, Compound ( 1 ) demonstrated a moderate anti‐inflammatory effect (34.82% at 1 mg/mL) compared to diclofenac (99.42% at 1 mg/mL) and has a consistent ability to dock into the binding sites of all selected inflammatory targets, with high binding affinities (−7.2 to −8.6 kcal/mol). Furthermore, the predicted physicochemical and drug‐like properties of Compound ( 1 ) showed a favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile with acceptable oral bioavailability. Thus, phloracetophenone 4‐ O ‐β‐ d ‐glucopyranoside could constitute a promising and safe therapeutic agent.